This proposal builds on previous work in Hawaii in which we showed that, for a given smoking history, Native Hawaiians have a lung cancer risk which is twice as great as that of Japanese. We propose a multidisciplinary investigation of the role of dietary and genetic factors in explaining the ethnic differences observed in Hawaii in the lung cancer risk associated with smoking. Much evidence suggests that dietary antioxidants may be protective against lung cancer. The genetically-determined ability to metabolize the antihypertensive drug debrisoquine,which varies widely among individuals and may also vary among ethnic groups, has been proposed as a marker for the ability to activate procarcinogens in tobacco smoke. We plan to conduct a population-based case-control study of 221 Hawaiian cases, 239 Japanese cases, 320 Caucasian cases and 780 population controls matched on sex, age and ethnicity. This study design will provide adequate power to test hypotheses relating sex- and ethnic- specific lung cancer risks to dietary intake of antioxidants (specifically, alpha-tocopherol, gamma-tocopherol, ascorbic acid, alpha- carotene, beta-carotene, lutein, lycopene, beta-cryptoxanthin) and fat, and to the debrisoquine metabolism deficiency genotype. The relative risks and distribution of etiologic factors will be compared among ethnic groups to estimate the fraction of interethnic risk differences attributable to these dietary and genetic factors. A quantitative dietary history assessing complete dietary intake, as well as a detailed smoking and occupational history, will be administered by trained interviewers in the subjects' homes. A fasting blood sample will also be obtained. DNA purified from leukocytes will be analyzed to characterize the debrisoquine metabolic genotype of cases and controls. Plasma from the controls will be analyzed for the dietary antioxidants above and for glutathione peroxidase and uric acid. This study may explain the high lung cancer risk of Native Hawaiians, a native American population with an unusually high cancer burden. It also offers a unique opportunity to elucidate the interactions of genes and lifestyle in the etiology of lung cancer, the most common cancer in the U.S. The findings may enable the targeting of intensive smoking control programs, as well as chemoprevention and screening trials, to persons at high risk and, thus, help increase the efficacy of cancer control efforts in Native Hawaiians and other ethnic/racial groups.